A Promising Advance in Polycythemia Vera Treatment: Rusfertide’s Potential to Reduce Phlebotomy Dependence

Author: Pratham Sarkar

According to the Cleveland Clinic (2024), polycythemia vera affects 1 to 3 people per 100,000 each year. This makes it a serious but rare disease. In over 95% of patients, the disorder is most often linked to a JAK2 V617F mutation. This mutation causes the bone marrow to produce too many red blood cells. Higher blood volume due to greater hematocrit increases the risk of heart disorders such as deep vein thromb

osis, heart attacks, and strokes. In addition to the risk of blood clots, polycythemia vera can cause severe symptoms. Symptoms include headaches, nocturnal sweats, stomach pain from an enlarged spleen, itching (particularly after warm showers), and persistent weariness.

Current Standard Treatments and Limitations

For the vast majority of PV patients, therapeutic phlebotomy remains the primary line of

Credits: National Cancer Institution

treatment, with the aim of maintaining hematocrit <45% in males and <42% in women.The procedure, akin to donating blood, physically decreases blood volume to lower cell mass and viscosity. While effective at decreasing clot risk, serial phlebotomies can cause iron deficiency with its attendant symptoms of fatigue, cognitive impairment, brittle nails, and restless legs syndrome (Leukemia & Lymphoma Society, 2024). Phlebotomy is typically combined with low-dose aspirin to decrease platelet aggregation and the risk of clot formation. In "high-risk" patients (generally > age 60 or with a history of clotting event), cytoreductive agents hydroxyurea or pegylated interferon alfa are added. Hydroxyurea suppresses the activity of the bone marrow but needs close monitoring for cytopenias and has the potential for long-term leukemogenic risks. Peginterferon alfa has been found to decrease JAK2 allele burden over time but can lead to flu-like symptoms and mood disturbances. Targeted therapy using ruxolitinib, a JAK1/JAK2 inhibitor, is reserved for hydroxyurea-resistant or intolerant patients. Although effective at symptom control and reduction of spleen size, it does not obviate the need for phlebotomy in many patients. With these limitations, a therapy that directly controls red blood cell production without marrow suppression or frequent phlebotomy would fill an unmet clinical need.

Rusfertide: Mechanism and Development 

Rusfertide (PTG-300) is a hepcidin mimic that works similarly to the liver-derived hormone hepcidin to restrict the amount of iron available for the development of red blood cells. Hepcidin regulates intestinal absorption and the release of stored iron. Iron availability affects PV's overproduction of red blood cells, which can reduce erythropoiesis. By controlling hematocrit without actually drawing blood, this "chemical phlebotomy" method seeks to improve patients' quality of life and possibly lessen the negative effects of iron deficiency (National Cancer Institute, 2024).

Clinical Trial Evidence 

A late-stage randomized controlled trial, reported in June 2025 by The Wall Street Journal, randomized 290 PV patients who were already being treated with standard therapy,

Credit: Patient Power

comprised of hydroxyurea or interferon in most cases. Patients were randomized to take rusfertide or placebo on top of their current regimen. Highlights were: 77% of rusfertide-treated patients did not need phlebotomy between weeks 20 and 32, compared to 33% for placebo. Mean number of phlebotomies over the 32-week study was 0.5 for rusfertide and 1.8 for placebo. Patients had reductions in symptoms common in PV, including fatigue, itching, night sweats, and abdominal pain. Most adverse effects were mild and consisted of injection site reactions, anemia, and fatigue. There were no major safety concerns during the period of the study. The study will be extended beyond that period, for as long as three years, to ascertain long-term safety and durability of hematocrit control. Fifty-two-week data is expected in late 2025, with a U.S. Food and Drug Administration (FDA) submission shortly thereafter.

Clinical Significance and Future Impact 

With the approval of rusfertide, it would become possible to reduce the application of the centuries-old practice of bloodletting in PV towards a pharmacologic strategy capable of maintaining hematocrit within safe ranges without exacerbating iron deficiency. This would benefit especially: Patients intolerant of frequent blood draws. While the initial findings are

Credits: Cancer Connect

promising, some questions remain. Long-term safety is a concern. Since rusfertide is meant for chronic treatment, it must show lasting benefits without unexpected side effects. Ongoing monitoring of current trials and real-world experiences after approval will determine rusfertide's final role in treating polycythemia vera (PV).Rusfertide takes a novel method to managing red blood cell formation by targeting iron metabolism specifically. Early clinical findings suggest that it may reduce the need for therapeutic phlebotomy, lessen symptom burdens, improve patient convenience, and possibly result in fewer adverse effects. If its long-term safety and efficacy are demonstrated, rusfertide could become a significant addition to PV treatment guidelines, enhancing the management of a disease that has been managed using outmoded ways for generations.

Works Cited

Abbott, Brianna. “New Polycythemia Vera Treatment Offers Hope for Patients Who Make Too Many Red Blood Cells.” WSJ, The Wall Street Journal, 9 June 2025, www.wsj.com/health/healthcare/polycythemia-vera-red-blood-cells-treatment-bed50266.

Cleveland Clinic. “Polycythemia Vera (PV) | Cleveland Clinic.” Cleveland Clinic, 2018, my.clevelandclinic.org/health/diseases/17742-polycythemia-vera.

John Hopkins Medicine. “Polycythemia Vera.” Www.hopkinsmedicine.org, www.hopkinsmedicine.org/health/conditions-and-diseases/polycythemia-vera.

Spindler, Shana. “Rusfertide Cuts Number of Needed Blood Draws to Treat PCV - NCI.” Www.cancer.gov, 2024, www.cancer.gov/news-events/cancer-currents-blog/2024/rusfertide-polycythemia-vera-fewer-phlebotomies.

“Treatment | Leukemia and Lymphoma Society.” Www.lls.org, www.lls.org/myeloproliferative-neoplasms/polycythemia-vera/treatment.

Weaver, Charles H. “Rusfertide Offers New Hope for Polycythemia Vera Patients.” CancerConnect, 4 June 2025, news.cancerconnect.com/rusfertide-offers-new-hope-for-polycythemia-vera-patients/.

“What Is Polycythemia Vera?” Www.patientpower.info, 7 July 2021, www.patientpower.info/myeloproliferative-neoplasms/what-is-polycythemia-vera.